The present invention relates to 1,6-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.
Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.
The current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.
Over time almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion, i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose; low primary and secondary failure rates; and preservation of islet cell function. The strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion.
Metabolism of glucose promotes the closure of ATP-dependent K+channels, which leads to cell depolarization and subsequent opening of Ca++channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose-stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, A., et al., Diabetes 47: 1426-1435 (1998)). The effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.
Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-dependent fashion (Komatsu, M., et al., Diabetes 46: 1928-1938, (1997)). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.
PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells. Three different PACAP receptor types (R1, R2, and R3) have been described (Harmar, A., et al., Pharmacol. Reviews 50: 265-270 (1998)). The insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++]i, and promoting the exocytosis of insulin-containing secretory granules.
Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Pat. No. 3,879,371). This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP-R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.
GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in xcex2-cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, M., et al., New Eng. J. Med. 326:1316-1322, (1992)) and with longer infusions improved the beta cell function to those of normal subjects (Rachman, J. et al., Diabetes 45: 1524-1530, (1996)). A recent report has shown that GLP-1 improves the ability of xcex2-cells to respond to glucose in subjects with impaired glucose tolerance (Byrne M., et al., Diabetes 47: 1259-1265 (1998)). All of these effects, however, are short-lived because of the short half-life of the peptide.
The invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders. Compounds of the invention include compounds of formula (II). 
wherein R1xe2x80x2 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R1xe2x80x2 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, NR11R12, C(xe2x95x90O)OR11, C(xe2x95x90O)NHR11, NHC(xe2x95x90O)R13, NHS(xe2x95x90O)2R13, S(xe2x95x90O)0-2R13, S(xe2x95x90O)2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, Oxe2x80x94Axe2x80x94R14, NR11R12; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or
R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10;
with the proviso for R1xe2x80x2 that when A is CH2, R9 is not optionally substituted biphenyl;
R2xe2x80x2 is selected from NR15R16, S(O)0-2R17, and OR17;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, Axe2x80x94R9, C(xe2x95x90O)R18, C(xe2x95x90O)NHR18, S(xe2x95x90O)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
R18 is Axe2x80x94R9;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or
R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, Axe2x80x94R9, or
R17 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10;
R3xe2x80x2 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R3xe2x80x2 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, Axe2x80x94OR19, Axe2x80x94NR19R20, and Axe2x80x94R20;
R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and 0, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R4xe2x80x2 is selected from xe2x95x90O, xe2x95x90S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10;
R5xe2x80x2, R7xe2x80x2, and R8xe2x80x2 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or
R5xe2x80x2, R7xe2x80x2, and R8xe2x80x2 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, Axe2x80x94R23, Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, S(xe2x95x90O)2R26, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR26, or Axe2x80x94C(xe2x95x90O)NR24R25, or
R5xe2x80x2, R7xe2x80x2, and R8xe2x80x2 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, Axe2x80x94R23, A(OR22)xe2x80x94R23, NR27R28, Axe2x80x94NR27R28, Axe2x80x94Qxe2x80x94R29, Qxe2x80x94R29, Qxe2x80x94Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, and Axe2x80x94C(xe2x95x90O)NR24R25;
Q is selected from O and S(xe2x95x90O)0-2;
R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)xe2x80x94R23 that when R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)xe2x80x94R23, and Axe2x80x94R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, Axe2x80x94R23, C(xe2x95x90O)R24, C(xe2x95x90O)OR26, C(xe2x95x90O)NR25R30, S(xe2x95x90O)2R26, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, and Axe2x80x94C(xe2x95x90O)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)xe2x80x94R23, and Axe2x80x94R23, or
R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10;
R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, Axe2x80x94R23, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, Axe2x80x94C(xe2x95x90O)NR24R25, Axe2x80x94NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
and pharmaceutically acceptable salts thereof.
Another aspect of the invention includes compounds of formula (II), wherien R1xe2x80x2 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and Axe2x80x94R9, or
R1xe2x80x2 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, NR11R12, C(xe2x95x90O)OR11, C(xe2x95x90O)NHR11, NHC(xe2x95x90O)R13, NHS(xe2x95x90O)2R13, S(xe2x95x90O)0-2R13, S(xe2x95x90O)2NHR11, cycloalky of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, Oxe2x80x94Axe2x80x94R14, NR11R12; or
R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or
R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10;
with the proviso for R1xe2x80x2 that when A is CH2, R9 is not optionally substituted biphenyl;
R2xe2x80x2 is NR15R16;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, Axe2x80x94R9, C(xe2x95x90O)R8, C(xe2x95x90O)NHR18, S(xe2x95x90O)2NHR18;
R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or
R18 is Axe2x80x94R9;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and Axe2x80x94R9, or
R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R3xe2x80x2 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or
R3xe2x80x2 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, Axe2x80x94OR19, Axe2x80x94NR19R20 and Axe2x80x94R20;
R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R4xe2x80x2 is selected from xe2x95x90O, xe2x95x90S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, all of which may be substituted with 1-3 of R10;
R5xe2x80x2 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or
R5xe2x80x2 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, Axe2x80x94R23, Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, S(xe2x95x90P)2R26, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, or Axe2x80x94C(xe2x95x90O)NR24R25, or
R5xe2x80x2 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, Axe2x80x94R23, A(OR22)xe2x80x94R23, NR27R28, Axe2x80x94NR27R28, Axe2x80x94Qxe2x80x94R29, Qxe2x80x94R29, Qxe2x80x94Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, and Axe2x80x94C(xe2x95x90O)NR24R25;
Q is selected from O and S(xe2x95x90O)0-2;
R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or
R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)xe2x80x94R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)xe2x80x94R23, and Axe2x80x94R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and Axe2x80x94R23, or
R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, Axe2x80x94R23, C(xe2x95x90O)R24, C(xe2x95x90O)OR26, C(xe2x95x90O)NR25R30, S(xe2x95x90O)2R26, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, and Axe2x80x94C(xe2x95x90O)NR24R25, or
R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)xe2x80x94R23, and Axe2x80x94R23, or
R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and
R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, Axe2x80x94R23, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, Axe2x80x94C(xe2x95x90O)NR24R25, Axe2x80x94NR27R28, or
R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(xe2x95x90O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(xe2x95x90O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10.
R7xe2x80x2 and R8xe2x80x2 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or
R7xe2x80x2 and R8xe2x80x2 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(xe2x95x90O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(xe2x95x90O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, Axe2x80x94R23, Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, S(xe2x95x90O)2R26, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, or Axe2x80x94C(xe2x95x90O)NR24R25, or
R7xe2x80x2 and R8xe2x80x2 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, Axe2x80x94R23, A(OR22)xe2x80x94R23, NR27R28, Axe2x80x94NR27R28, Axe2x80x94Qxe2x80x94R29, Qxe2x80x94R29, Qxe2x80x94Axe2x80x94NR24R25, C(xe2x95x90O)R24, C(xe2x95x90O)OR24, C(xe2x95x90O)NR24R25, Axe2x80x94C(xe2x95x90O)R24, Axe2x80x94C(xe2x95x90O)OR24, and Axe2x80x94C(xe2x95x90O)NR24R25;
and pharmaceutically acceptable salts thereof.
Methods of the invention provide for the treatment or prevention of diabetes, inlcuding Type 1 and Type 2 diabetes, and related disorders by administration of a compound of the invention. Related disorders include maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X.
In other embodiments, methods of the invention provide for the administration of a compound of the invention in combination with a PPAR agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an xcex1-glucosidase inhibitor or insulin. PPAR agonist includes rosiglitazone and pioglitazone. Sulfonylureas include glibenclamide, glimepiride, chlorpropamide, and glipizide. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide. xcex1-glucosidase inhibitors include acarbose, miglitol and voglibose. A hepatic glucose output lowering compound is metformin.
In another embodiment, methods of the invention provide for the administration of a compound of the invention in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug. Anti-obesity drugs include a xcex2-3 agonist, a CB-1 antagonist, and a lipase inhibitor.
In another embodiment of the invention, methods are provided for the treatment or prevention of secondary causes of diabetes, such as glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.
Finally, methods of the invention provide for increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, by administering a compound of the invention. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
The present invention therefore provides compounds and methods for the treatment of diabetes and related disorders. These and other aspects of the invention will be more apparent from the following description and claims.
The invention relates generally to naphthyridine derivatives of the formula 
wherein one of U, X, Y and Z is nitrogen and the others are Cxe2x80x94R, where R is hydrogen or a substituent such as R5xe2x80x2, R7xe2x80x2 or R8xe2x80x2, as described above for formula (II). R1xe2x80x2, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 are as defined above for formula (II). The invention relates to compounds of formula (II), as described above, and to compounds of formula (I) 
wherein R1, R2, R3, R4, R5, R6 and R7 correspond to R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2, R5xe2x80x2, R7xe2x80x2 and R8xe2x80x2, respectively, of formula (II). Such compounds may be used in the treatment of diabetes and related disorders.
In one embodiment, the invention relates to compounds of formula (II), as described above. In another embodiment, the invention relates to compounds of formula (II), wherein R1xe2x80x2 is phenyl, which may be substituted with 1-3 of R10, R2xe2x80x2 is NR15R16, R3xe2x80x2 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or R3xe2x80x2 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, Axe2x80x94OR19, Axe2x80x94NR19R20 and Axe2x80x94R20, and R4xe2x80x2 is xe2x95x90O.
In another embodiment, the invention relates to methods of treating diabetes and related disorders by administration of compounds of formula (II). Preferred methods relate to the treatment of Type 2 diabetes. In methods of the invention, compounds of formula (II) may be administered in combination with PPAR agonist, insulin sensitizers, sulfonylureas, insulin secretagogues, metformin, xcex1-glucosidase inhibitors and insulin. In another embodiment, compounds of formula (II) are administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, an anti-hypertensive drug or an anti-obesity drug.
In other methods of the invention, compounds of formula (II) are administered to treat or prevent secondary causes of diabetes or to increase the sensitivity of pancreatic beta cells to an insulin secretagogue.
The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
In general, compounds of Formula (I) (R4 is xe2x95x90O) may be prepared from the appropriately substituted nicotinic acid through several routes summarized in Flow Diagram I to IV. Compounds of Formula (II) (R4xe2x80x2 is xe2x95x90O) may be prepared from the appropriately substituted nicotinic acid through the route summarized in Flow diagram V. The close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II). The routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid. 
The nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001, 475-477; J. Prakt. Chem. 2002, 33; Eur. J. Org. Chem. 2001, 1371; J. Org. Chem. 2000, 65, 4618; J. Med. Chem. 1997, 40, 2674; Bioorg. Med. Chem. Lett. 2000, 10, 1151; U.S. Pat. No. 3,838,156, etc.). 
Further manipulations of Formula (I) (when R4 is xe2x95x90O) and (II) (when R4xe2x80x2 is xe2x95x90O) could lead to more diversely substituted compounds. These manipulations include aromatic nucleophilic substitutions, metal-mediated couplings, reductions, oxidations, amide formations, etc.
Flow Diagram VII illustrates alkylation, and amide, urea, and sulfonamide formations in Formula (I) when R2xe2x95x90NHR16. Similar transformations could be carried out in Formula (II) when R2xe2x95x90NHR16. 
Flow Diagram VIII and IX illustrate transformations at R3 in Formula (I). These transformations could also be applied to R3xe2x80x2 in Formula (II). 
Flow Diagram X illustrates manipulations of R4 in formula (I), which could also be used on R4xe2x80x2 in formula (II). 
Flow Diagram XI illustrates manipulations of R6 in formula (I). These manipulations could also be applied to R5 and R7 in formula (I), R5xe2x80x2, R7xe2x80x2, and R8xe2x80x2 in formula (II). 
Flow Diagram XII illustrates manipulations on R7 of formula (I). These manipulations could also be applied to R5 in formula (I), R5xe2x80x2 and R7xe2x80x2 in formula (II). 
Flow Diagram XIII illustrates manipulations on R5 of formula (I). These manipulations could also be applied to R7 in formula (I), R5xe2x80x2 and R7xe2x80x2 in formula (II). 
Flow Diagram XIV illustrates the transformations of some fuinctional groups which are present in Formula (I) or (II). 
Alternative Forms of Novel Compounds
Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
(a) The Stereoisomers
The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
(b) The Pharmaceutically-Acceptable Salts
Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.
(c) The Tautomers
Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.
(d) The Protected Acids and the Conjugate Acids
The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
(e) The Prodrugs
The present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see xe2x80x9cPharmaceutical Dosage Form and Drug Delivery Systemsxe2x80x9d (Sixth Edition), edited by Ansel et al., publ. by Williams and Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman""s The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which is hereby incorporated by reference).
Dosages and Treatment Regimen
Dosage levels of the compounds of this invention typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily. On the basis of mg/kg daily dose, either given in a single dose or in divided doses, dosages typically range from about 0.001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg.
The total daily dose of each drug can be administered to the patient in a single dose, or in multiple subdoses. Typically, subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day. Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the diabetic condition.
The dosage regimen to prevent, treat, give relief from, or ameliorate a diabetic condition or disorder, or to otherwise protect against or treat a diabetic condition with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Pharmaceutical Compositions
For the prophylaxis or treatment of the conditions and disorders referred to above, the compounds of this invention can be administered as the compound per se. Alternatively, pharmaceutically-acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to that of the parent compound.
The compounds of the present invention also can be administered with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient. The carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound(s) based on a total weight of the dosage form. Other pharmacologically active substances can also be present, including other compounds useful in the treatment of a diabetic condition.
The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended. The active compounds and compositions, for example, may be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules, generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient. In the case of pharmaceutically acceptable salts, the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. If administered by mouth, the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
Oral delivery of the compounds of the present invention can include formulations, as are well known in the art, to provide immediate delivery or prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast-dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like. Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitor(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the inhibitor(s) with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations for parenteral administration, for example, may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Pharmaceutically acceptable carriers encompass all the foregoing and the like. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.
Methods of Use
The present invention also includes methods for the treatment of diabetes and related diseases and conditions. One such method comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of formula (II).
Compounds of formula (II) may be used in methods of the invention to treat diseases, such as diabetes, including both Type 1 and Type 2 diabetes. Such methods may also delay the onset of diabetes and diabetic complications. Other diseases and conditions that may be treated or prevented using compounds of formula (II) in methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40 (1994)), Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11:299 (1994)), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1) S5 (1999)), impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796 (1991)), gestational diabetes (Metzger, Diabetes, 40:197 (1991), and metabolic syndrome X.
Compounds of formula (II) may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1), S5 (1999)). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, xcex2-adrenergic agents, xcex1-interferon and drugs used to treat HIV infection.
The methods and compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.
Compounds of formula (II) may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, xcex1-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the compound of formula (II). Insulin includes both long and short acting forms and formulations of insulin. PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof. For example, PPAR agonist may inlcude agonists of PPAR-xcex1, PPAR-xcex3, PPAR-xcex4 or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide. xcex1-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of formula (II) include acarbose, miglitol and voglibose. Insulin sensitizers that may be useful in treating diabetes when administered with a compound of formula (II) include thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of formula (II) include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of formula (II) include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty-acid derivatized GLP-1 and exendin. In one embodiment of the invention, compounds of formula (II) are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue.
Compounds of formula (II) may also be used in methods of the invention in combination with anti-obesity drugs. Anti-obesity drugs include xcex2-3 agonists, CB-1 antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).
Compounds of formula (II) may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Compounds of formula (II) may also be used in combination with anti-hypertensive drugs, such as, for example, xcex2-blockers and ACE inhibitors.
Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of formula (I) in combination with an insulin sensitizer and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
Terms
As used herein, various terms are defined below.
When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles xe2x80x9caxe2x80x9d, xe2x80x9canxe2x80x9d, xe2x80x9cthexe2x80x9d and xe2x80x9csaidxe2x80x9d are intended to mean that there are one or more of the elements. The terms xe2x80x9ccomprisingxe2x80x9d, xe2x80x9cincludingxe2x80x9d and xe2x80x9chavingxe2x80x9d are intended to be inclusive and mean that there may be additional elements other than the listed elements.
The term xe2x80x9csubjectxe2x80x9d as used herein includes mammals (e.g., humans and animals).
The term xe2x80x9ctreatmentxe2x80x9d includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject""s condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
The phrase xe2x80x9ctherapeutically-effectivexe2x80x9d means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that the subject item is appropriate for use in a pharmaceutical product.
The term xe2x80x9cprodrugxe2x80x9d includes a compound that is a drug precursor that, following administration to a subject and subsequent absorption, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.
The following definitions pertain to the structure of the compounds: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified, for example, alkyl of 1-8 carbon atoms or C1-C8 alkyl. The use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definition of terms controls and conventional stable atom valences are presumed and achieved in all formulas and groups.
When symbols such as xe2x80x9cAxe2x80x94Qxe2x80x94Rxe2x80x9d is used, it refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group xe2x80x9cAxe2x80x94Qxe2x80x94Rxe2x80x9d is any position on group A to form a stable structure. Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.
When symbols such as xe2x80x9cA(ORxe2x80x2)xe2x80x94Rxe2x80x9d is used, it refers to a group which is formed by susbstituting group A with both group ORxe2x80x2 and group R and the attachment of this group xe2x80x9cA(ORxe2x80x2)xe2x80x94Rxe2x80x9d is any position on group A to form a stable structure. Group ORxe2x80x2 and group R maybe linked to any position on group A to form a stable structure.
The term xe2x80x9chalogenxe2x80x9d refers to a halogen radical selected from fluoro, chloro, bromo or iodo.
The term xe2x80x9calkylxe2x80x9d refers to a saturated aliphatic hydrocarbon radical. xe2x80x9cAlkylxe2x80x9d refers to both branched and unbranched alkyl groups. Examples of xe2x80x9calkylxe2x80x9d include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. This term is examplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), 1,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated xe2x80x9cAlkxe2x80x9d. It should be understood that any combination term using an xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d prefix refers to analogs according to the above definition of xe2x80x9calkylxe2x80x9d. For example, terms such as xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
The term xe2x80x9chaloalkylxe2x80x9d refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in examplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro. The term xe2x80x9chaloalkoxyxe2x80x9d refers to haloalkyl groups linked to a second group via an oxygen atom.
The term xe2x80x9calkenylxe2x80x9d refers to a mono or polyunsaturated aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond. xe2x80x9cAlkenylxe2x80x9d refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of xe2x80x9calkenylxe2x80x9d include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms. Other examples include alkenyl groups which are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to a mono or polyunsaturated aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond. xe2x80x9cAlkynylxe2x80x9d refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of xe2x80x9calkynylxe2x80x9d include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms. Other examples include alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to the mono- or polycyclic structures of xe2x80x9ccycloalkylxe2x80x9d where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include morpholino, pyrazino, tetrahydrofurano, and the like.
The term xe2x80x9cheterocycloalkenylxe2x80x9d refers to the mono- or polycyclic structures of xe2x80x9ccycloalkenylxe2x80x9d where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.
The term xe2x80x9ccycloalkyloxyxe2x80x9d refers to a monovalent radical of the formula xe2x80x94O-cycloalkyl, i.e., a cycloalkyl group linked to a second group via an oxygen atom.
The term xe2x80x9cacylxe2x80x9d refers to a monovalent radical of the formula xe2x80x94C(xe2x95x90O)-alkyl and xe2x80x94C(xe2x95x90O)-cycloalkyl, i.e., an alkyl or cycloakyl group linked to a second group via caronyl group C(xe2x95x90O), wherein said alkyl maybe further substituted with cycloalkyl, aryl, or heteroaryl. Examples of acyl groups include xe2x80x94C(xe2x95x90O)Me (acetyl), xe2x80x94C(xe2x95x90O)CH2-cyclopropyl (cyclopropylacetyl), xe2x80x94C(xe2x95x90O)CH2Ph (phenylacetyl), and the like.
The term xe2x80x9carylxe2x80x9d refers to 6-10 membered mono- or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term xe2x80x9carylxe2x80x9d refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, xe2x80x94NHMe and xe2x80x94N(Me)2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. All the above subtsitutions can further be substituted with optionally selected groups to form a stable structure. It may be abbreviated xe2x80x9cArxe2x80x9d. It should be understood that any combination term using an xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d prefix refers to analogs according to the above definition of xe2x80x9carylxe2x80x9d. For example, terms such as xe2x80x9caryloxyxe2x80x9d, xe2x80x9carylthioxe2x80x9d, xe2x80x9carylaminoxe2x80x9d refer to aryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
The term xe2x80x9cheteroarylxe2x80x9d refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heteroaryl contains 1-10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. The term xe2x80x9cheteroarylxe2x80x9d includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, xe2x80x94NHMe and xe2x80x94N(Me)2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. Examples of xe2x80x9cheteroarylxe2x80x9d include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Terms such as xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9cheteroarylthioxe2x80x9d, xe2x80x9cheteroarylaminoxe2x80x9d refer to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.
The terms xe2x80x9coptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted arylxe2x80x9d means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
Abbreviations and Acronyms
When the following abbreviations are used throughout the disclosure, they have the following meaning: